This invention relates to methods for manufacturing 3-hydroxy-3-methylbutanoic acid (HMB) in high yield, in large batch amounts, with high quality, and in a relatively short amount of time.
Several reports have recently appeared disclosing that HMB exhibits significant efficacy for nitrogen retention and muscle building in humans. See Nissen et al., U.S. Pat. No. 5,348,979; Phillips, Muscle Media 2000 (October 1995), xe2x80x9cHMB New Drug-Free Mass Builder;xe2x80x9d these and all other references cited herein are expressly incorporated by reference as if fully set forth in their entirety herein. Promoting nitrogen retention has therapeutic importance for trauma patients and for patients showing loss of protein due to stress conditions. Moreover, administration of HMB has been reported to enhance the immune response of mammals (Nissen et al., U.S. Pat. No. 4,992,470), and to increase lean tissue development in meat-producing animals (Nissen et al., U.S. Pat. Nos. 5,087,472 and 5,028,440).
The structure 
of HMB is reproduced below.
Despite these several reports on the beneficial properties of HMB, this substance is currently available only in small quantities due to the lack of a suitable synthetic procedure for commercial production of HMB. In fact, during recent years, several chemical manufacturing companies have sought to develop a high output synthetic process for HMB. These attempts have been based on the reactions described in Coffman et al., Journal of the American Chemical Society 80:2882-2887 (1958); Wagner and Zook, Synthetic Organic Chemistry 422-423, 458 (1953); March, Advanced Organic Chemistry, Rxn. 2-43, 567 (3d ed. 1985); Blatt, Organic Synthesis 2:428-429, 526-527 (1943); Blatt, Organic Synthesis 3:302-303 (1955) Blatt, Organic Synthesis 5:8-9 (1973). According to this procedure, diacetone alcohol (DIA) is subjected to alkaline sodium hypochlorite oxidation to produce HMB.
In a previous attempt at producing a commercially viable procedure, an average yield of 0.26 pounds of HMB per pound of DIA was achieved, with the most efficient batch achieving a yield of 0.325 pounds of HMB per pound of DIA. The reaction was typically run in a reactor no greater than 200 gallons, with an average charge of 156 gallon of bleach and about 95 pounds of DIA, to produce about 25 pounds HMB per batch. This process was plagued by an inability to control reaction temperature, and this inability mandated the use of small batch sizes. This process moreover failed to provide access to HMB in quantities sufficient to enable therapy on humans or animals. Thus, a need exists for an HMB manufacturing process that will allow production of high quantities of high quality HMB, and will permit HMB manufacture on a large scale, has been achieved through the improvements described herein.
This invention is based on the unexpected discovery that, in a large scale process for production of HMB using a main reaction tank for oxidation of an HMB precursor, the batch size, yield, and quality of product can be dramatically increased by use of an external heat exchanger with constant flow loop to maintain a reaction temperature of below 15xc2x0 C. The apparatus of the invention includes a reaction tank having a first temperature probe within the reaction tank, and an associated reaction mixture recycling cooling loop. The cooling loop includes an outlet passage from the reaction tank in fluid communication with an external heat exchanger, and further includes an inlet passage which connects the external heat exchanger to the reaction tank. This system allows the reaction mixture to flow from the reaction tank through the outlet passage to the heat exchanger, and then through the inlet passage back to the reaction tank. A second temperature probe is typically provided on the outlet passage. The external heat exchanger may include a cooling inlet pipe and a cooling outlet pipe which connects the external heat exchanger to an auxiliary chiller. One or more additional temperature probes may be included on the cooling inlet pipe, cooling outlet pipe, or both. Moreover, the inlet passage, which provides flow of reactant from the external heat exchanger back to the reaction tank, may be equipped with a further temperature probe.
The chemical process of the invention provides a method to produce HMB from 4-hydroxy-4-methyl-2-pentanone (diacetone alcohol, or DIA). According to the method of the invention, the reaction tank is charged with a solution of oxidant, preferably hypochlorite, hypobromite, or hypoiodite. The reaction tank and external heat exchanger are then operated in order to cool the solution to a temperature below 15xc2x0 C., more preferably below 12xc2x0 C., more preferably below 10xc2x0 C., more preferably below 8xc2x0 C., more preferably below 6xc2x0 C., and most preferably below 5xc2x0 C. Once the appropriate temperature has been achieved as indicated by one or more of the temperature probes, DIA is fed into the reaction tank while maintaining the solution at a temperature of 15xc2x0 C. or below. During this step, it is important to carefully monitor the temperature, and to regulate the rate of addition of DIA so that the temperature does not rise above 15xc2x0 C. The oxidation of DIA is an exothermic reaction, and therefore uncontrolled addition of DIA will cause a rise in temperature of the reaction mixture. If the reaction temperature is allowed to rise above 15xc2x0 C., byproducts which may include acetic acid and/or diol will be formed, and this side reaction will, of course, reduce the yield and amount of the desired product HMB. We have observed that at xe2x88x9210xc2x0 C. the ratio of HMB to diol byproduct is 5.9:1, while at 5xc2x0 C. the ratio is 5.0-5.3:1, whereas when the temperature is uncontrolled, the ratio becomes 2:1. After the reaction of DIA is complete, the reaction tank is either acidified to produce HMB or treated with a salt to produce a salt thereof.
In accordance with the method herein disclosed, we have been able to achieve an average yield of 0.44 pounds of HMB per pound of DIA, a significant and unexpected 70% improvement over the earlier used process. The highest batch yield with our procedure has been 0.50 pounds of HMB per pound of DIA. Not only has yield improved, but addition of DIA can be conducted at a rate 10-20 times faster than the rate used in the earlier process. In the improvement described herein, more than ten times as much DIA was added in a 4- to 8-hour period as was added in an 8-hour period during the earlier process. This improvement in the reactant addition rate is also significant and unexpected.
In a preferred embodiment, the reaction tank is charged with hydrochloric acid after the reaction of DIA is completed, and the pH is adjusted to approximately 3.5 or lower. Thereafter, HMB is extracted with an organic solvent, and the organic solvent may be removed by vacuum distillation in order to concentrate HMB. In certain embodiments, the extraction solvent is ethyl acetate. In another embodiment, the heat exchanger is a carbate heat exchanger, and includes a cooling tank holding a cooling fluid, a cooling inlet passage, and a cooling outlet passage, all in fluid communication with the external heat exchanger. The cooling fluid can be a solution of methanol and water, and the cooling tank is optimally maintained at a temperature of lower than xe2x88x9210xc2x0 C., more preferably lower than xe2x88x9220xc2x0 C. Thus, according to the HMB manufacturing process disclosed herein, the reaction mixture may be pumped through the external heat exchanger at a rate of at least 80 gallons/minute, more preferably 90 gallons/minute, more preferably 100 gallons/minute, more preferably 110 gallons/minute or more. During charging of the tank with DIA, the rate of addition of DIA may be adjusted based on temperature readings at the first and second temperature probes, which refer to the temperature probe within the reaction tank and the temperature probe on the outlet passage.
In another embodiment, the reaction tank is equipped with an adjustable decant tube to facilitate rapid extraction of organic solvent. The adjustable decant tube includes an elongated tubular member which extends through an opening at the top of the reaction tank and down into the reaction tank, terminating in a xe2x80x9cJxe2x80x9d section which allows a clean decant of organic solvent. The decant tube includes, at its top portion, an attachment which allows connection of the tube to a pulley system which is used to raise and lower the adjustable decant tube within the reaction tank as described below in more detail.